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Background
This rare soft tissue tumor is part of a clinical-pathologic syndrome characterized by renal phosphate wasting. Removal of the tumor results in reduction and eventual disappearance of the signs and symptoms. These patients present with bone and muscle pain and severe muscle weakness. The most common sites of the tumors include the bone and soft tissues but many organs have been implicated.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Oncogenic osteomalacia INCIDENCE Rare AGE RANGE-MEDIAN Adults
Mean 33 years
Range 5-63 years
DISEASE ASSOCIATIONS CHARACTERIZATION BONE TUMORS
Oncogenic osteomalacia: a clinicopathologic study of 17 bone lesions.Park YK, Unni KK, Beabout JW, Hodgson SF.
Section of Surgical Pathology, Kyung Hee University Medical Center, Korea.
J Korean Med Sci 1994 Aug;9(4):289-98 Abstract quote Oncogenic osteomalacia is an unusual and rare clinicopathologic syndrome characterized by mesenchymal tumors that apparently produce osteomalacia and biochemical abnormalities consisting of hypophosphatemia, normocalcemia, and increased levels of alkaline phosphatase.
We collected from the Mayo Clinic files and from our consultation files the records for 17 cases of osteomalacia associated with bone lesions. There were five cases of fibrous dysplasia, three of hemangiopericytoma, and two of phosphaturic mesenchymal tumor. There was one case each of osteosarcoma, chondroblastoma, chondromyxoid fibroma, malignant fibrous histiocytoma, giant cell tumor, metaphyseal fibrous defect, and hemangioma.
In this study we can figure out that the most common characteristic histologic features of our cases were hemangiopericytomatous vascular proliferation, fine lace-like stromal calcification, and stromal giant cells.
In most of the cases, the clinical and biochemical symptoms and signs resolved soon after complete resection of the lesion. When the lesion recurred or metastasized, the symptoms and signs also recurred.
CENTRAL NERVOUS SYSTEM TUMOR
A neuroendocrine cause of oncogenic osteomalacia.Stone MD, Quincey C, Hosking DJ.
Metabolic Unit, University Hospital, Nottingham, U.K.
J Pathol 1992 Jun;167(2):181-5 Abstract quote All definite cases of oncogenic osteomalacia have, until now, been classified as mesenchymal tumours.
We report here a case of oncogenic osteomalacia caused by a spinal tumour. Microscopically, it resembled the mixed connective tissue variant of previously described phosphaturic tumours. Immunohistochemical studies, however, showed the tumour cells to be positive for low molecular weight cytokeratin (CAM 5.2), S100 protein, PGP 9.5, and synaptophysin.
Electron microscopy demonstrated neurosecretory granules. The histopathological findings strongly suggest that this is a neuroendocrine tumour.
Oncogenic osteomalacia associated with a meningeal phosphaturic mesenchymal tumor. Case report.David K, Revesz T, Kratimenos G, Krausz T, Crockard HA.
Department of Surgical Neurology, National Hospital for Neurology and Neurosurgery, London, England.
J Neurosurg 1996 Feb;84(2):288-92 Abstract quote A 60-year-old woman suffered from hypophosphatemic osteomalacia secondary to a frontal intracranial tumor.
Oral administration of phosphate and 1-alpha-hydroxyvitamin D3 provided only temporary symptomatic relief. A computerized tomography (CT) scan of the patient's head revealed a large subfrontal tumor attached to the dura. Following removal of the tumor, the patient's hypophosphatemia subsided; her level of 1,25-dihydroxyvitamin D3, which was undetectable preoperatively, returned to normal, and she had symptomatic improvement. Three years later, decreasing levels of phosphate and 1,25-dihydroxyvitamin D3 indicated tumor recurrence, before it was detected by CT scan.
Histological examination of the tumor provided the diagnosis of "mixed connective tissue variant of phosphaturic mesenchymal tumor." The characteristic histological features of this relatively rare entity are discussed.
This is the first report of a surgically treated intracranial phosphaturic mesenchymal tumor that caused oncogenic osteomalacia.
HEAD AND NECK
Oncogenic osteomalacia caused by a phosphaturic mesenchymal tumor of the oral cavity: a case report.Yang IM, Park YK, Hyun YJ, Kim DY, Woo JT, Kim SW, Kim JW, Kim YS, Choi YK.
Division of Endocrinology, Kyunghee University, School of Medicine, Seoul Korea.
Korean J Intern Med 1997 Jan;12(1):89-95 Abstract quote We report a case of oncogenic osteomalacia associated with a phosphaturic mesenchymal tumor in a 31-year-old woman. She was presented with severe generalized bone and muscle pain and was restricted to bed. She lost 20 cm in height over the 8 years since she had first noticed a pain in her thigh. A walnut-sized, hard, soft tissue tumor was found very easily beside her lower molar teeth.
Radiologic examination revealed a remarkable decrease in bone density and multiple pathologic fractures of spine, femur and phalangeal bones. Severe hypophosphatemia, hyperphosphaturia, low plasma 1,25-dihydroxyvitamin D3 level and high plasma PTH level were disclosed at presentation. Histomorphometric examination revealed an extensive area of unmineralized osteoid and little mineralizing activity. A pharmacologic dose of 1 alpha-hydroxyvitamin D3 or or 1,25-dihydroxyvitamin D3 slightly increased the serum phosphate level and renal tubular reabsorption of phosphate, and slightly decreased plasma PTH level without any symptomatic improvement.
Histologic examination of the tumor revealed a mixed connective tissue tumor that consisted of central woven bones and surrounding primitive spindle cells with prominent vascularities. After removal of the tumor, all biochemical, hormonal and radiologic abnormalities disappeared with remarkable symptomatic improvement.
Oncogenic osteomalacia: case report and review of head and neck associated tumours.Gonzalez-Compta X, Manos-Pujol M, Foglia-Fernandez M, Peral E, Condom E, Claveguera T, Dicenta-Sousa M.
Department of Oto-rhino-laryngology, Ciutat Sanitaria Universitaria de Bellvirge, Barcelona, Spain.
J Laryngol Otol 1998 Apr;112(4):389-92 Abstract quote Oncogenic osteomalacia is an uncommon syndrome characterized by mineral metabolism abnormalities that disappear after the resection of an associated tumour. Head and neck is the second most frequent location of these tumours.
We describe a case with an ethmoido-frontal phosphaturic mesenchymal tumour and review oncogenic osteomalacia-associated tumours. Among 21 cases found, 57 per cent affected the sinonasal area and 20 per cent the mandible.
The diagnosis of the tumour lasted a mean of 4.7 years from the onset of osteomalacia, and most of them showed a significant vascular component. An aggressive surgical approach is recommended.
HEMANGIOMAS BONE
Tumorous phosphaturic osteomalacia. Report of a case associated with multiple hemangiomas of bone.Daniels RA, Weisenfeld I.
Am J Med 1979 Jul;67(1):155-9 Abstract quote A case of osteomalacia associated with hypophosphatemia, decreased tubular reabsorption of phosphorus, hyperphosphaturia and renal glycosuria with associated bone pain and myopathy is presented. The patient was found to have multiple osteolytic lesions of bone which, on biopsy, proved to be sclerosing hemangiomas of bone.
Treatment with oral phosphate and vitamin D effected a diminution in his symptoms of bone pain and muscular weakness. The literature on hypophosphatemic phosphaturic osteomalacia associated with mesenchymal tumors is reviewed.
It has been suggested that certain mesenchymal tumors elaborate a yet to be identified humoral substance which decreased synthesis of 1 alpha, 25-dihydroxycholecalciferol causing decreased tubular reabsorption of phosphorus, hyperphosphaturia, hypophosphatemic osteomalacia and hypophosphatemic myopathy.
LUNG
Tumor-induced osteomalacia.Schapira D, Ben Izhak O, Nachtigal A, Burstein A, Shalom RB, Shagrawi I, Best LA.
Department of Rheumatology, Rambam Medical Center, Haifa, Israel.
Semin Arthritis Rheum 1995 Aug;25(1):35-46 Abstract quote Tumor-induced (oncogenic) osteomalacia is a rare clinicopathologic entity in which the clinical signs and symptoms of osteomalacia and the specific laboratory abnormalities of hypophosphatemia, hyperphosphaturia, and low serum levels of 1,25(OH)2 vitamin D are associated with the finding of a neoplastic process in the patient. To date, less than 100 cases of oncogenic osteomalacia have been described.
We report a new case of adult-onset hypophosphatemic osteomalacia leading to the discovery of an asymptomatic phosphaturic mesenchymal lung tumor. Complete resection of the pulmonary neoplasia was followed by rapid normalization of the laboratory findings and clinical remission. The clinical, laboratory, and histopathologic spectrum of tumor-induced osteomalacia is presented, and the postulated mechanism of this condition is discussed in light of the relevant literature.
The presence of occult neoplasms should be considered in cases of unexplained adult osteomalacia, with the physician's efforts being rewarded by the dramatic cure that follows excision of the tumor.
MESENCHYMAL CHONDROSARCOMA
Oncogenic osteomalacia associated with a mesenchymal chondrosarcoma.Stone E, Bernier V, Rabinovich S, From GL.
Clin Invest Med 1984;7(3):179-85 Abstract quote A patient with phosphaturic osteomalacia without chemical or pathological evidence of hyperparathyroidism and subnormal urinary cyclic AMP excretion was treated with vitamin D and phosphates for 9 months with partial improvement of osteomalacia, but not phosphaturia.
Subsequent removal of a mesenchymal chondrosarcoma of the foot led to prompt resolution of phosphaturia and healing of the osteomalacia. Although 1,25-dihydroxyvitamin D levels were not obtained before vitamin D therapy, the levels noted during continued severe phosphaturia preoperatively were not lower than those obtained several months postoperatively during the healing phase. Studies done 1 year after tumor removal showed normalization of phosphaturia, urinary cyclic AMP, and bone histology.
We suggest that the tumor elaborated products which promoted nonparathyroid mediated phosphate excretion independently from any effects on vitamin D metabolism.
PROSTATE CANCER Prostate cancer-induced oncogenic hypophosphatemic osteomalacia.
Nakahama H, Nakanishi T, Uno H, Takaoka T, Taji N, Uyama O, Kitada O, Sugita M, Miyauchi A, Sugishita T, et al.
Fifth Department of Internal Medicine, Hyogo College of Medicine, Japan.
Urol Int 1995;55(1):38-40 Abstract quote A 65-year-old male with prostate carcinoma showed mild hypocalcemia of 7.9 mg/dl, marked hypophosphatemia of 1.7 mg/dl, hyperphosphaturia (tubular reabsorption of phosphorus 43% and tubular threshold for phosphorus of 0.6 mg/dl), low serum 1,25 (OH)2D level of less than 5 pg/ml and osteomalacia indicated by a marked increase of relative osteoid volume and fractional formation rate in the undecalcified section.
Oncogenic osteomalacia due to prostatic carcinoma with suppression of 1,25 (OH)2D production and phosphaturia was suggested.
RICKETS
Phosphaturic mesenchymal tumor-induced rickets.Reyes-Mugica M, Arnsmeier SL, Backeljauw PF, Persing J, Ellis B, Carpenter TO.
Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, USA.
Pediatr Dev Pathol 2000 Jan-Feb;3(1):61-9 Abstract quote We describe two prepubertal girls with oncogenic rickets. The first patient, 9 years of age, presented with recent-onset lower-extremity pain. The second girl, presented at 4 years of age following a 9-month period of muscle weakness, bone pain, and poor linear growth. Laboratory analyses in both patients revealed hypophosphatemia and hyperphosphaturia; elevated circulating alkaline phosphatase activity was present in one of them.
Radiographic evidence of a generalized rachitic process was evident in both cases. Computerized tomography of the paranasal sinuses and facial bones in patient 1 revealed a small lesion eroding through the inner table of the left mandibular ramus. Microscopic examination of this mass revealed a spindle cell neoplasm with chondroid material, dystrophic calcification, and both osteoclast-like and fibroblast-like cells. Prominent vascularity and marked atypia were present. These features are consistent with a phosphaturic mesenchymal tumor of the mixed connective tissue variant.
In the second patient, computerized tomography revealed a lytic lesion located in the right proximal tibia, with histologic features consistent with a phosphaturic mesenchymal tumor of the nonossifying fibroma-like variant. Resection of each tumor resulted in rapid correction of the phosphaturia and healing of the rachitic abnormalities.
A careful search for small or occult tumors should be carried out in cases of acquired phosphaturic rickets.
PATHOGENESIS CHARACTERIZATION GENERAL
Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism.De Beur SM, Finnegan RB, Vassiliadis J, Cook B, Barberio D, Estes S, Manavalan P, Petroziello J, Madden SL, Cho JY, Kumar R, Levine MA, Schiavi SC.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Bone Miner Res 2002 Jun;17(6):1102-10 Abstract quote Oncogenic osteomalacia (OOM) is associated with primitive mesenchymal tumors that secrete phosphaturic factors resulting in low serum concentrations of phosphate and calcitriol, phosphaturia, and defective bone mineralization.
To identify overexpressed genes in these tumors, we compared gene expression profiles of tumors resected from patients with OOM and histologically similar control tumors using serial analysis of gene expression (SAGE).
Three hundred and sixty-four genes were expressed at least twofold greater in OOM tumors compared with control tumors. A subset of 67 highly expressed genes underwent validation with an extended set of OOM and control tumors using array analysis or reverse-transcription polymerase chain reaction (RT-PCR).
Ten of these validated genes were consistently overexpressed in all OOM tumors relative to control tumors. Strikingly, genes with roles in bone matrix formation, mineral ion transport, and bone mineralization were highly expressed in the OOM tumors.
ADHR GENE
The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting.White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, Meitinger T, Strom TM, Juppner H, Econs MJ.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
J Clin Endocrinol Metab 2001 Feb;86(2):497-500 Abstract quote The gene mutated in autosomal dominant hypophosphatemic rickets (ADHR), a phosphate wasting disorder, has been identified as FGF-23, a protein that shares sequence homology with fibroblast growth factors (FGFs). Patients with ADHR display many of the clinical and laboratory characteristics that are observed in patients with oncogenic hypophosphatemic osteomalacia (OHO), a disorder thought to arise by the secretion of a phosphate wasting factor from different mesenchymal tumors.
In the present studies, we therefore investigated whether FGF-23 is a secreted factor and whether it is abundantly expressed in OHO tumors. After transient transfection of OK-E, COS-7, and HEK293 cells with the plasmid encoding full-length FGF-23, all three cell lines efficiently secreted two protein species into the medium that were approximately 32 and 12 kDa upon SDS-PAGE and subsequent Western blot analysis using an affinity-purified polyclonal antibody to FGF-23. Furthermore, Northern blot analysis using total RNA from five different OHO tumors revealed extremely high levels of FGF-23 mRNA, and Western blot analysis of extracts from a sixth tumor detected the 32 kDa FGF-23 protein species.
In summary, FGF-23, the gene mutated in ADHR, is a secreted protein and its mRNA is abundantly expressed by several different OHO tumors. Our findings indicate that FGF-23 may be a candidate phosphate wasting factor, previously designated "phosphatonin".
DENTIN MATRIX PROTEIN 1 Expression of dentin matrix protein 1 in tumors causing oncogenic osteomalacia.
Toyosawa S, Tomita Y, Kishino M, Hashimoto J, Ueda T, Tsujimura T, Aozasa K, Ijuhin N, Komori T.
Department of Oral Pathology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.
Mod Pathol. 2004 May;17(5):573-8. Abstract quote
Oncogenic osteomalacia, which is characterized by renal phosphate wasting, low serum 1, 25-dihydroxyvitamin D, and osteomalacia, is caused by mesenchymal neoplasms that are termed phosphaturic mesenchymal tumors (PMTs). As PMTs are usually small and lack specific histological features, the pathological identification of PMTs is difficult.
Dentin matrix protein 1 (DMP1) is an acidic phosphoprotein expressed in mineralized tissues including bone, tooth, and hypertrophic cartilage. Increased expression of DMP1 gene in PMTs has been reported by using differential cDNA screening.
In the present study, DMP1 expression in PMTs and other soft tissue tumors was analyzed immunohistochemically to verify its utility in the differential diagnosis of PMTs. Anti-DMP1 polyclonal antibody was raised against the C-terminal sequence of DMP1. Three cases with PMTs and 11 other soft tissue tumors (two malignant hemangiopericytomas, three solitary fibrous tumors, three synovial sarcomas, and three malignant peripheral nerve sheath tumors) were analyzed for DMP1 expression. DMP1 expression was observed in all of the three cases with PMTs, but never found in other soft tissue tumors examined. DMP1 was detected in the extracellular matrix with myxomatous features or around capillary vessels, and in dystrophic calcified sites.
Paranuclear DMP1 staining in the tumor cells was also observed. These findings indicate that DMP1 immunohistochemistry is a useful tool for identifying PMTs.FIBROBLASTIC GROWTH FACTOR 23 (FGF23)
Fibroblast growth factor-23 is the phosphaturic factor intumor-induced osteomalacia and may be phosphatonin.Fukumoto S, Yamashita T.
Department of Laboratory Medicine, University of Tokyo, Tokyo.
Curr Opin Nephrol Hypertens 2002 Jul;11(4):385-9 Abstract quote PURPOSE OF REVIEW: Three hypophosphatemic diseases, X-linked dominant hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced rickets/osteomalacia (TIO), show very similar clinical features including hypophosphatemia due to renal phosphate wasting. Because of some evidence that XLH and TIO are caused by a humoral mechanism, the presence of a phosphate-regulating hormone, phosphatonin, was hypothesized. The causative factor of TIO has been thought to be a strong candidate for phosphatonin. In this review, we summarize recent findings concerning a humoral factor which causes TIO, and discuss the nature of phosphatonin.
RECENT FINDINGS: The PHEX gene and fibroblast growth factor (FGF)-23 were identified as responsible genes for XLH and ADHR, respectively. In addition, FGF-23 was cloned as a gene abundantly expressed in a responsible tumor for TIO and was shown to reproduce almost all characteristics of TIO when overexpressed in mice. Furthermore, FGF-23 was proteolytically processed between Arg179 and Ser180, and all mutations found in ADHR existed in this proteolytic consensus site. Mutant FGF-23 proteins were resistant to the processing and seem to have somehow increased biological activity. There is not yet enough evidence that FGF-23 is phosphatonin, and the relation between PHEX and FGF-23 is unclear.
SUMMARY: FGF-23 plays important roles in the development of hypophosphatemic diseases. These findings will certainly contribute to the development of new diagnostic and therapeutic maneuvers for hypophosphatemic diseases.
HUMORAL PHOSPHATURIC FACTOR
Oncogenic osteomalacia: evidence for a humoral phosphaturic factor.Wilkins GE, Granleese S, Hegele RG, Holden J, Anderson DW, Bondy GP.
Department of Medicine, St. Paul's Hospital, Vancouver, British Columbia, Canada.
J Clin Endocrinol Metab 1995 May;80(5):1628-34 Abstract quote Oncogenic osteomalacia is a syndrome characterized by phosphaturia, hypophosphatemia, reduced vitamin D levels, and osteomalacia. The cause is not known, but all patients have had a tumor; usually of mesenchymal origin. Removal of the tumor reverses the metabolic abnormalities.
We report a patient with osteomalacia, severe hypophosphatemia, elevated alkaline phosphatase, low 1,25-dihydroxyvitamin D3, and phosphaturia. A tumor was identified in the infratemporal fossa. The tumor was removed, and all of the biochemical abnormalities resolved over the subsequent 8 months. The bone density returned to normal values. The tumor had the appearance of a paraganglioma and was used to establish a cell culture line called JH-55. Electron microscopy of the original tumor and the JH-55 cells demonstrated the presence of neurosecretory granules. A bioassay using opossum kidney cells was used to evaluate phosphate transport. Conditioned medium from the JH-55 cells inhibited phosphate reabsorption by the kidney tubular cells. Maximal inhibition required a 24-h incubation period and was not altered by the presence of an inhibitor of protein synthesis (10 micrograms/mL cycloheximide). Immunoassays revealed no detectable PTH-related peptide or intact PTH in the JH-55 medium.
The cause of this paraneoplastic syndrome is not known, but all of the evidence is consistent with the action of a hormone that produces phosphaturia. This putative factor is distinct from other hormones that cause phosphaturia.
PHEX GENE
Phosphate wasting in oncogenic osteomalacia: PHEX is normal and the tumor-derived factor has unique properties.Nelson AE, Hogan JJ, Holm IA, Robinson BG, Mason RS.
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, Australia.
Bone 2001 Apr;28(4):430-9 Abstract quote
Oncogenic osteomalacia (OOM) is characterized by renal phosphate wasting and abnormal metabolism of vitamin D, somewhat similar to the phenotype of X-linked hypophosphatemic rickets (HYP).DNA from OOM tumor cells was analyzed for mutations in the PHEX gene, which is mutated in HYP. Screening for mutations by single-strand conformation polymorphism analysis and subsequent sequencing of all the exons revealed no mutations. Conditioned media from long-term cultures of OOM tumor cells were used to further characterize the physical properties of the phosphate-regulating factor and its mechanism of action. Inhibition of OK 3B2 cell renal phosphate transport by conditioned media was dose-dependent and maximal after 20 h. This time course differed from that of parathyroid hormone (PTH). The bioactivity was stable to mild acid and alkali treatment and freeze drying and was retained in the aqueous phase following organic solvent extraction. The activity was not suppressed by heat or by treatment with trypsin but was suppressed by the protease papain and had an apparent molecular weight of < 5000. No change was detected in the expression of type II sodium/phosphate cotransporter (NaPi) mRNA in OK 3B2 cells in response to conditioned media, unlike the reduction seen in Hyp mice. In the presence of colchicine or cytochalasin D, the inhibitory response to conditioned media was reduced, similar to the effect of these agents on the response to PTH. Cycloheximide also suppressed the inhibitory response of conditioned media, but not the response to PTH.
These studies indicate that mutations in the PHEX gene are unlikely to be responsible for OOM and suggest that the tumor-derived factor that inhibits phosphate uptake is a small protein that does not downregulate type II NaPi mRNA, and requires an intact cytoskeleton and protein synthesis for activity.
PHOSPHATONIN
Tumor-induced osteomalacia and the regulation of phosphate homeostasis.Kumar R.
Departments of Medicine, Biochemistry, and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Bone 2000 Sep;27(3):333-8 Abstract quote Tumor-induced osteomalacia (TIO) is a rare and unique syndrome characterized by hypophosphatemia, excessive urinary phosphate excretion, reduced 1,25-dihydroxyvitamin D concentrations, and osteomalacia. Removal of the tumor is associated with a cure of the lesion.
Several laboratories have now shown that conditioned medium derived from cultures of such tumors contain a small, heat-sensitive substance ("phosphatonin") of <25,000 daltons that specifically inhibits sodium-dependent phosphate transport in cultured renal proximal tubular epithelia. This substance does not increase cyclic adenosine monophosphate (cAMP) formation in tubular epithelial cells and does not increase cAMP excretion in urine. A substance with similar properties is present in the circulation of patients on hemodialysis. A syndrome with a remarkably similar biochemical phenotype, namely, X-linked hypophosphatemic rickets (XLH), also has a circulating factor with properties similar, if not identical, to those of the tumor-derived factor, "phosphatonin." The molecular defect in XLH has been shown to be due to a mutant endopeptidase, PHEX, whose substrate might be "phosphatonin."
Hypophosphatemia and other biochemical abnormalities in TIO are due to excessive production of "phosphatonin" with normal PHEX function, whereas the biochemical abnormalities in XLH are caused by a mutant PHEX enzyme that fails to process "phosphatonin."
FGF23, hypophosphatemia, and rickets: has phosphatonin been found?
Strewler GJ.
Department of Medicine, Veterans Affairs Boston Healthcare System and Harvard Medical School, Boston, MA 02132, USA.
Proc Natl Acad Sci U S A 2001 May 22;98(11):5945-6
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC Octreotide scanning in the detection of a mesenchymal tumour in the pubic symphysis causing hypophosphataemic osteomalacia.
Moran M, Paul A.
University Department of Orthopaedic Surgery, Manchester Royal Infirmary, UK.
Int Orthop 2002;26(1):61-2 Abstract quote Oncogenic hypophosphataemic osteomalacia is a rare condition. The causative tumour is often difficult to locate.
Primary tumours have been reported in the head and neck, skeleton, and soft tissue. Octreotide scanning was used in this case and detected a mesenchymal tumour in the pubic symphysis.
Bone and In-111 octreotide imaging in oncogenic osteomalacia: a case report.Garcia CA, Spencer RP.
Division of Nuclear Medicine, Department of Diagnostic Imaging and Therapeutics, University of Connecticut Health Center, Farmington, Connecticut 06030-2804, USA.
Clin Nucl Med 2002 Aug;27(8):582-3 Abstract quote Osteoporosis associated with aging is considered the most common cause of bone mineral loss. Osteomalacia, abnormal bone loss with excess osteoid formation, is another cause. A 46-year-old man was examined for chronic hip and lower extremity pain that had not been relieved by nonsteroidal anti-inflammatory drugs or steroids. A bone scan revealed multiple foci of activity. The serum calcium level was normal, but phosphorus values were low.
These results did not correspond with the indications for typical hyperparathyroid disease, so another cause was sought. An In-111 octreotide scan showed a focus in the right humeral head. At surgery, a phosphaturic tumor of mesenchymal origin was partially resected.
Oncogenic osteomalacia is related to secretion of a phosphaturic material from a fibroblast growth factor.
LABORATORY MARKERS Renal phosphate wasting (hyperphosphaturia)
Hypophosphatemia
Normal serum calcium
Decreased serum 1,25 dihydroxyvitamin D3SERUM PHOSPHATE
Diagnosis of a patient with oncogenic osteomalacia using a phosphate uptake bioassay of serum and magnetic resonance imaging.Nelson AE, Mason RS, Robinson BG, Hogan JJ, Martin EA, Ahlstrom H, Astrom G, Larsson T, Jonsson K, Wibell L, Ljunggren O.
Cancer Genetics Department, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney 2065, Australia.
Eur J Endocrinol 2001 Oct;145(4):469-76 Abstract quote A previously healthy man with no family history of fractures presented with muscle pain, back pain and height loss. Investigations revealed hypophosphataemia, phosphaturia, undetectable serum 1,25-dihydroxyvitamin D and severe osteomalacia on bone biopsy, suggestive of a diagnosis of oncogenic osteomalacia. Thorough physical examination did not locate a tumour.
Support for the diagnosis was obtained by detection of phosphate uptake inhibitory activity in a blinded sample of the patient's serum using a renal cell bioassay. On the basis of detection of this bioactivity, a total body magnetic resonance (MR) examination was performed. A small tumour was located in the right leg. Removal of the tumour resulted in the rapid reversal of symptoms and the abnormal biochemistry typical of oncogenic osteomalacia. Inhibitory activity was also demonstrated using the bioassay in serum from two other patients with confirmed or presumptive oncogenic osteomalacia, but not in serum from two patients with hypophosphataemia of other origin.
This is the first case to be reported in which the diagnosis of oncogenic osteomalacia was assisted by demonstration of inhibitory activity of the patient's serum in a renal cell phosphate bioassay that provided an impetus for total body MR imaging.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL
Hypophosphatemic oncogenic osteomalacia: report of three new cases.Papotti M, Foschini MP, Isaia G, Rizzi G, Betts CM, Eusebi V.
Dipartimento di Scienze Biomediche e Oncologia Umana, Universita di Torino, Italia.
Tumori 1988 Oct 31;74(5):599-607 Abstract quote Three cases of connective tissue tumors causing hypophosphatemic osteomalacia are reported and the literature is reviewed. In two of our patients the tumors were completely excised with total disappearance of the symptoms. In one case a total excision was not possible and the symptoms of this patient have not completely disappeared.
The substance responsible for the syndrome has not been identified yet, but probably interferes with vitamin D renal hydroxylation, thus causing osteomalacia. As more than 30 per cent of cases of this condition have been reported in the last 5 years, it is suggested that these tumors are more frequent than previously believed.
VARIANTS STRESS FRACTURES
Oncogenic osteomalacia presenting as bilateral stress fractures of the tibia.Ohashi K, Ohnishi T, Ishikawa T, Tani H, Uesugi K, Takagi M.
Department of Radiology, St. Marianna University Hospital, Kawasaki City, Kanagawa, Japan.
Skeletal Radiol 1999 Jan;28(1):46-8 Abstract quote We report on a patient with bilateral stress fractures of the tibia who subsequently showed classic biochemical features of oncogenic osteomalacia.
Conventional radiographs were normal. MR imaging revealed symmetric, bilateral, band-like low-signal lesions perpendicular to the medial cortex of the tibiae and corresponding to the only lesions subsequently seen on the bone scan. A maxillary sinus lesion was subsequently detected and surgically removed resulting in prompt alleviation of symptoms and normalization of hypophosphatemia and low 1,25-(OH)2 vitamin D3. The lesion was pathologically diagnosed as a hemangiopericytoma-like tumor.
Patients with oncogenic osteomalacia may present with stress fractures limited to the tibia, as seen in athletes. The clue to the real diagnosis lies in paying close attention to the serum phosphate levels, especially in patients suffering generalized symptoms of weakness and not given to unusual physical activity.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Classification usually based on system of Weidner and Santa Cruz
Primaitive-appearing mixed connective tissue tumors (Phosphaturic mesenchymal tumor-mixed connective tissue variant)
Osteoblastoma-like tumors
Nonossifying fibroma-like tumors
Ossifying fibroma-like tumors
Most Osteomalacia-associated Mesenchymal Tumors Are a Single Histopathologic Entity: An Analysis of 32 Cases and a Comprehensive Review of the Literature.
Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, Econs MJ, Inwards CY, Jan De Beur SM, Mentzel T, Montgomery E, Michal M, Miettinen M, Mills SE, Reith JD, O'Connell JX, Rosenberg AE, Rubin BP, Sweet DE, Vinh TN, Wold LE, Wehrli BM, White KE, Zaino RJ, Weiss SW.
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; dagger Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC; double dagger Department of Pathology, Indiana University School of Medicine, Indianapolis, IN; section sign Department of Pathology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy; paragraph sign Department of Pathology, University of Bologna, Rizzoli Institute, Bologna, Italy; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN; dagger dagger Department of Anatomic Pathology, Mayo Clinic, Rochester, MN
Am J Surg Pathol. 2004 Jan; 28(1): 1-30. Abstract quote SUMMARY: Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors.
Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed.
The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma.
Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors.
Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.
Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets.Weidner N, Santa Cruz D.
Cancer 1987 Apr 15;59(8):1442-54 Abstract quote Reported are the pathologic features of 17 mesenchymal tumors documented as causing osteomalacia or rickets. Although these tumors were histologically polymorphous, they were classifiable into four morphological groups.
In the first group there were ten unique tumors showing mixed connective tissue features and containing variably prominent vascular and/or osteoclast-like giant-cell components. Tumors of this group also displayed focal microcystic changes, osseous metaplasia, and/or poorly developed cartilaginous areas. The cartilaginous areas sometimes showed considerable dystrophic calcification.
With one exception, all tumors of this group occurred in soft tissue and demonstrated benign clinical behavior. The single malignant tumor originated in bone, recurred locally, and metastasized to lung.
The tumors comprising the remaining three groups (six tumors) occurred in bone, demonstrated benign clinical behavior, and were grouped according to their close resemblance to tumors known to occur in bone, that is osteoblastoma-like (four tumors), nonossifying fibroma-like (two tumors), and ossifying fibroma-like (one tumor).
Phosphaturic mesenchymal tumor, mixed connective tissue variant (oncogenic osteomalacia).Tsujimura T, Sakaguchi K, Aozasa K.
Department of Pathology, Sumitomo Hospital, Osaka, Japan.
Pathol Int 1996 Mar;46(3):238-41 Abstract quote A case of tumor-induced phosphaturic osteomalacia in a 54 year old man is reported. The patient was admitted because of progressive muscle spasms with pain and weakness in the bilateral thighs. Laboratory data showed hypophosphatemia, decreased tubular resorption of phosphate (TRP), a low 1,25-dihydroxyvitamin D level, and a high serum alkaline phosphatase level. Radiologic examinations revealed multiple lesions of osteomalacia in the ribs, and a small mass in the lower posterior mediastinum. After removal of the tumor, clinical symptoms disappeared and hypophosphatemia, decreased TRP, and the 1,25-dihydroxyvitamin D level were corrected.
Microscopical examination revealed that the tumor was composed of mature adipose tissues, osseous tissues, and primitive stromal zones including osteoclast-like giant cells, non-mineralized woven bone, and various sized blood vessels.
Patho-physiologic observations suggested that the tumor secreted some humoral substances inhibiting 25-hydroxyvitamin D-1 alpha-hydroxylase activity, renal phosphate resorption, and parathyroid hormone production.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE Usually vimenting positive
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES BONE TUMORS
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS RECURRENCE
Recurrent malignant variant of phosphaturic mesenchymal tumor with oncogenic osteomalacia.Ogose A, Hotta T, Emura I, Hatano H, Inoue Y, Umezu H, Endo N.
Department of Orthopedic Surgery, Niigata University School of Medicine, Asahimachi 1, Niigata 951-8510, Japan.
Skeletal Radiol 2001 Feb;30(2):99-103 Abstract quote Phosphaturic mesenchymal tumor is a rare neoplasm which causes osteomalacia or rickets. The tumor typically follows a benign clinical course. Even in the rare malignant cases, local recurrence and distant metastasis are uncommon.
We report on an example of a malignant phosphaturic mesenchymal tumor which recurred several times over 16 years concurrently causing hypophosphatemia, bone pain, and osteomalacia. Following each surgery, symptoms and hypophosphatemia improved. The patient died of disease 17 years after the first surgery.
Histologically, the initial tumor was composed of small spindle cells with clusters of giant cells, prominent blood vessels, poorly formed cartilaginous areas, and crystalline material. Cytological atypia was minimal. Following multiple recurrences, the tumor demonstrated areas of high-grade sarcoma exhibiting marked pleomorphism, numerous mitotic figures, and p53 overexpression.
This case illustrates the potential lethality of incompletely removed phosphaturic mesenchymal tumors.
TREATMENT SURGERY
Osteomalacia cured by surgery.Furco A, Roger M, Mouchet B, Richard O, Martinache X, Fur A.
Department of Internal Medicine, Hauts-Clos Hospital, 101 Avenue Anatole France, 10003 Cedex, Troyes, France
Eur J Intern Med. 2002 Feb;13(1):67-69 Abstract quote Oncogenic osteomalacia is an uncommon syndrome characterized by bone pain, proximal muscle weakness, hypophosphatemia, hyperphosphaturia, and a low concentration of 1,25-dihydroxyvitamin D.
This syndrome is induced by a tumor, usually benign, of mesenchymal origin and resolves after its excision. We report a case of an oncogenic osteomalacia caused by a small mesenchymal tumor of the tendon sheath of the foot, a localized form of tenosynovial giant cell tumor.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Weedon D. Weedon's Skin Pathology. Second Edition. Churchill Livingstone. 2002.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
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